This is a multi-disciplinary _Bioengineering Research Grants_ (BRG) proposal in response to PA-10-009, with design-driven and discovery-driven elements. It is based on a hypothesis that is gaining in popularity, that the progression of a number of neurological disorders is rooted in homeostatic plasticity that has become maladaptive. These can be classified as de-afferentation disorders, where disruptive synchronized population bursting activity develops across days or weeks, in CNS tissue whose inputs have been greatly reduced or eliminated by white matter damage, stroke, or damage to sensory receptors or peripheral nerves. Low-frequency, high-amplitude electrical discharges from population bursting can manifest as seizures, chronic pain, dystonia, tinnitus, or other disabling symptoms, depending on which part of the nervous system has become hyper-excitable after deafferentation. Pharmacological treatments are often completely ineffective. This has lead many to propose therapies that involve direct, localized brain stimulation with implanted electrodes or transcranial magnetic stimulation. Optogenetics provides a much more localized and specific way to stimulate brain tissue, because it can render defined neural cell types sensitive to light of specific colors. Wit it, light can either activate or silence targeted neurons in an effort to normalize aberrant neural activity. Based on a successful closed-loop approach to quieting seizure-like population bursting in cultured cortical networks with multi-electrode array stimulation, this project is to develop and optimize a closed-loop optogenetic tool to gain control over homeostatic plasticity mechanisms, and to reverse the tendency of deafferented tissue to express synchronized bursting. This _Population Clamp_ will employ extracellular recording from multi-electrode array substrates as the feedback signal, to rapidly and continuously adjust pulses of colored light, selectively activating and inhibiting different neuron types, to maintain a desired activity level. Cortical networks expressing population discharges due to the deafferentation typical of in vitro preparations will be clamped to different activity set----points for days. Homeostatic responses, such as changes in synaptic strength, will be monitored with intracellular recording and extracellular measures of population activity. Combinations of optogenetic constructs, directed at excitatory pyramidal neurons or inhibitory interneurons using adeno-associated viral vectors, will be compared in terms of their ability to serve as handles by which homeostatic plasticity can be manipulated. Feedback control algorithms will be developed that enable the most effective and enduring remission of population bursting, while enhancing measures of network function, such as the mutual information between complex light input and spiking output. By providing an accessible and manipulable test bed for studying different constructs and parameters, the Optogenetic Population Clamp will pave the way for gene-therapeutic treatments of a variety of neurological disorders that employ closed-loop light stimulation via implanted fiber optics. PUBLIC HEALTH RELEVANCE: The way the brain regulates its sensitivity to input can cause devastating symptoms when input gets cut off, due to stroke, epilepsy, deafness in the inner ear, loss of a limb, or brain damage from physical trauma. Brain tissue can become too sensitive to its own spontaneous activity, causing seizures, ringing in the ears, chronic pain, or other serious neurological problems. This proposal is to create a new and powerful tool to actively correct this type of over-sensitivity and restore more normal neural activity patterns.